The increasing incidence of obesity is a major health issue facing the world and increased understanding of body weight regulation may lead to effective strategies to combat obesity and related disorders, such as diabetes. The sex hormone, estrogen, plays a beneficial role in maintaining normal body weight as women show dramatically increased risks for developing obesity and diabetes when they enter menopause. Hormone replacement therapy may be a way to reduce these risks, but actions of estrogen via its receptors in the peripheral tissues cause unwanted effects, such as cancer and heart diseases. Thus, one objective of the proposed study is to determine whether the anti-obesity effects of estrogen are mediated by one estrogen receptor isoform, ER(, expressed by specific populations of brain cells, namely POMC neurons and SF1 neurons. To this end, we will generate mouse models with ER( deleted selectively in POMC neurons and/or SF1 neurons, and assess whether the metabolic benefits induced by estrogen are abrogated in these animals. We will also generate mice whose POMC or SF1 neurons lack activity of PI3 kinase, which is an intracellular molecule activated by estrogen. By assessing effects of estrogen in these mice, we will determine if the PI3 kinase is required for estrogenic actions on energy balance. Thus, the proposed study will not only advance our understanding about the mechanisms by which sex hormone regulates brain functions to provide a coordinated regulation of body weight, but also help identify rationale targets for developing more specific estrogen therapies that provide metabolic benefits with no or fewer side effects. PUBLIC HEALTH RELEVANCE: The hormone replacement therapy with estrogen may be used to greatly reduce risks of development of obesity and metabolic syndrome in women. However, due to the broad actions of estrogen in the body, the metabolic benefits by estrogen are often associated with unwanted side effects, such as breast cancer and heart diseases. Using the state-of-art technology, we propose to identify the critical brain sites and intracellular molecules that mediate the anti-obesity effects of estrogen, and therefore results from this study will provide rational targets for the development of novel estrogen therapies that combat obesity and diabetes with no or few side effects.